Rocky Mountain spotted fever is a neglected tropical disease in Latin America

Rocky Mountain spotted fever (RMSF), a severe and extraordinarily lethal infectious disease, has emerged as a widespread public health crisis among predominantly vulnerable populations in several countries of Latin America, particularly evident in northern Mexico. Historically, RMSF has gained less attention than many other tropical infectious diseases, resulting in insufficient allocations of resources and development of capabilities for its prevention and control in endemic regions. We argue that RMSF fulfills accepted criteria for a neglected tropical disease (NTD). The relative neglect of RMSF in most Latin American countries contributes to disparities in morbidity and mortality witnessed in this region. By recognizing RMSF as an NTD, an increased public policy interest, equitable and more appropriate allocation of resources, scientific interest, and social participation can ameliorate the impact of this potentially treatable disease, particularly in vulnerable populations.


Introduction
Rocky Mountain spotted fever (RMSF), a tick-borne infectious disease (TBDs) caused by the gram-negative bacterium Rickettsia rickettsii, is transmitted by hard ticks of the genera Dermacentor, Haemaphysalis, Rhipicephalus, and Amblyomma in the family Ixodidae.Until the beginning of the 21st century, RMSF was considered a rare and sporadic infection in most countries of the Western Hemisphere.For reasons that remain unclear, RMSF reemerged during the last 25 years in multiple communities of the southwestern United States, and even more dramatically, across several towns and cities in several states of northern Mexico, where it now exists as hyperendemic disease in peri-domestic settings [1][2][3].The public health implications of a distinct zoonotic cycle involving free-roaming and stray dogs that support enormous populations of the vector tick species, Rhipicephalus sanguineus sensu lato, are profound.RMSF is a life-threatening disease that is no longer rare or sporadic in these regions.
Historically, high frequencies of fatal RMSF have been recorded throughout the Americas.Outbreaks of the disease are increasingly occurring among vulnerable populations, with disproportionately involving persons living in poverty and children [1,2].Contemporarily, casefatality rates (CFRs) from 20% to 57.5% are now documented in areas where the disease is hyperendemic [2,4,5] that are as high, or higher, than many of other lethal infectious diseases identified by the World Health Organization (WHO), including malaria, tuberculosis, HIV, invasive meningococcal disease, and dengue hemorrhagic fever [6].
Another salient and ominous feature of RMSF is the frequency of long-term sequelae experienced among patients who survive severe disease, which can include permanent cognitive deficits and gangrenous loss of digits or appendages (Fig 1) [1].The daunting morbidity and mortality associated with RMSF can incur enormous medical and indirect costs on lowincome communities where this disease is endemic.
Despite underestimation of its magnitude in Latin America, [2] that is already listed as a part of a heterogeneous group of rickettsial diseases of the PLoS neglected tropical diseases (NTD) [7] and although the impact of severe and fatal cases is commensurate with, or exceeds, the metrics of many of other infectious diseases, the RMSF is not recognized by WHO as an NTD [8,9].An interplay of structural and technical barriers can explain the current status of the disease in the region.

A) Poverty and socially disadvantaged populations
Poverty has been identified as a key determinant for most rickettsial diseases [10] and this is particularly evident with RMSF in Mexico and other countries of Latin America where increased tick exposure, higher morbidity, and greater severity of clinical manifestations occur among economically disadvantaged groups.All of that leading to a higher rate of fatal outcomes in people from socially marginalized communities, mainly in Latin American countries [1,2].Vulnerable populations including people living in poverty, children, pregnant women, migrants, indigenous people, and older adults are even at higher risk of death and long-term RMSF sequelae when compared with other demographic groups in endemic regions [4,[11][12][13][14][15][16].

B) Neglect of scientific research
Although RMSF was identified and characterized in the early 20th century, its contemporary body of research is limited when compared to other TBDs such as Lyme disease and human anaplasmosis [10].In addition, a regional gap in scientific publications can be clearly identified and our review of the PubMed database revealed 70% of 1,803 papers concerning RMSF published during 1916 to 2023 were studies predominantly performed in the US, while in Latin America, together with Brazil and Mexico represented 11% of all results for the disease.Although this database is among the largest medical repositories worldwide, it only includes 198 reviews, 2 systematic reviews and just 1 meta-analysis concerning the disease and reveals few multicenter collaborations across the Americas.

C) Budgetary constraints
The impact of financial shortcomings is summarized in 2 negative effects on magnitude and impact of RMSF.On one hand, it hinders the acquisition of laboratory equipment and reagents to establish a clinically actionable and epidemiologically critical diagnosis, as well as hampering access to intravenous doxycycline and other drugs needed for the management of severe cases, which impedes an accurate estimation of the true incidence rate and contributes to the unacceptable fatality rates observed in some Mexican populations [5,17,18].On the other hand, economic constraints halts implementation of effective public health measures such as those targeting tick exposure, control of the canine population, sanitary improvement of dwellings, and community-based education campaigns in rural localities and urban slums, which are fundamental for reducing fatal outcomes of RMSF in endemic areas [11,12].

D) Political support
An example of how important political support is to alleviate the deleterious impact of RMSF, occurred in April 2015 in Me ´xico.Due to the significant increase in cases and deaths caused by the disease, the Ministry of Health issued a national declaration of epidemiological emergency, which made a call for strengthening epidemiological surveillance, medical care, and prevention of the disease [19].Among other benefits of this declaration, public hospitals and clinicians had access for the first time to intravenous doxycycline to care for severe cases, and some regions had financial support for dog spaying and neutering campaigns and acquisition of acaricides.Thus, political support is at the heart of the success of national and regional programs for prevention and control of RMSF.

A) Weak epidemiological surveillance systems
The geographic distribution of RMSF is restricted to the Americas, with Mexico [2,5,17,18], Brazil [4,13], and the US [1,20] constituting the countries with the heaviest recognized burden, but there is an uncertainty about the actual magnitude and distribution of the disease, as most statistics come from small scientific reports and less from governmental agencies.
The benefits of good epidemiological surveillance systems (ESS) are well accepted for disease tracking and estimation of its impact on defined populations.Mexico has an established national ESS for monitoring the disease.In this system, 5,957 cases of RMSF and spotted fever group rickettsiosis (SFGR) were notified in the 1990 to 2022 period, [21] with the vast majority reported in Mexican states bordering with the US; in this region, vulnerable populations such as children, migrant day laborers, and older adults have been the most affected [2,5,17,18].Another salient example occurs in Brazil where 1,245 cases were confirmed during the 2007 to 2015 period with the majority being reported from the state of São Paulo [4]; moreover, the CFR increased from 19.2% to 40.2% in different states during the last decade [4,13].In spite of that, ESS targeting RMSF in Latin America are mostly based on passive models reflecting the occurrence only of notified cases, not actively looking prospectively for risk factors preceding the disease, which may underestimate the true regional burden of morbidity and mortality.

B) Poor community risk perception
A poor community risk perception of RMSF has been documented regarding exposures, clinical manifestations, and preventive measures [11,12].Difficult access to information about the relevance of certain risk factors including the distribution of infected ticks has a negative impact on the success of preventive campaigns for tick control and protection of natural and incidental hosts, including pet dogs.Such risk factors include travel history to endemic areas or the role of stray and free-roaming dogs, as well as the contact with wild hosts [1,2].

C) Insufficient laboratory diagnostic capacity
In several regions of Latin America, laboratory confirmation of R. rickettsii is not achieved because of (a) limited access to effective diagnostic technology; (b) difficulties to support entomological and epidemiological surveillance systems at the regional and local levels; and (c) funding obstacles that hinder the capacity to detect the pathogen in populations of ticks and hosts [22].
Laboratory methods and technologies to confirm infections with R. rickettsii form part of a complicated process that requires specific conditions to obtain a valid result either through the indirect immunofluorescence antibody (IFA) assay, which is the current gold standard, or by molecular biology techniques that are not usually available in clinical settings.The insufficient training of laboratory personnel and severe shortcomings of reagents and equipment, decrease the test validity and reliability, thus contributing to the underestimation of the RMSF burden [1,22].

D) Inadequate physician training
It is pivotal for a better understanding and management of the disease to improve physician's knowledge, attitudes, and practices (KAP) regarding RMSF.Importantly, several studies have documented medical gaps regarding the rapid use of doxycycline, education about preventive behaviors (i.e., avoiding contact with tick infested dogs, restricting dogs to roam freely), and diagnostic procedures, leading to delay in clinical diagnosis and initiation of treatment, which is associated with fatal outcomes [23,24].To bridge the gap in medical KAP, efforts need to stress the importance of integrating clinical and epidemiological characteristics of the disease with the understanding of the social determinants of health.

Fig 1 .
Fig 1. Clinical images of severe Rocky Mountain spotted fever in pediatric patients in northern Mexico.A) Petechiae and ecchymotic lesions on the right upper extremity of a 1-year-old female patient from Sonora, Mexico.B) Extensive cutaneous necrosis on the left lower extremity of a 7-yearold female patient, from Sonora, Mexico.C) Confluent petechial rash involving the thorax, abdomen, and upper extremities of an 18-year-old male patient from Sonora, Mexico.https://doi.org/10.1371/journal.pntd.0012276.g001